The present invention relates to new benzo[b]pyrano[3,2-h]acridin-7-one compounds.
The compounds of the invention are derivatives of acronycine, an alkaloid which has anti-tumour properties that have been demonstrated in experimental models (J. Pharm. Sci., 1966, 55 (8), 758-768). However, despite having quite a broad spectrum of activity, acronycine is of low potency and moderate activity. The solubility of the compound is, moreover, low, which limits its bioavailability, as well as its use in pharmaceutical compositions for administration by the intravenous route.
Various modifications have been made to the molecule, for example those described in J. Med. Chem., 1996, 39, 4762-4766 or EP 1 042 326, allowing a significant improvement in the potency, anti-tumour efficacy and solubility of the products. Nevertheless, anti-cancer therapeutic requirements call for the constant development of new anti-tumour agents with the aim of obtaining medicaments that are simultaneously more active and better tolerated. More specifically, solid tumours constitute a major problem for anti-cancer chemotherapy because of their intrinsic and/or acquired resistance to existing compounds. Moreover, certain compounds which are shown to be highly active with respect to certain cell lines are found to be inactive with respect to other cell lines or indeed toxic. It is therefore of prime importance to have access to the widest range of compounds exhibiting powerful cytotoxic activity in order to have available the most effective treatments for the totality of tumour disorders, together with limited secondary effects and the longest desirable action over time.
Besides the fact that the compounds of the invention are new, they have surprising in vitro and in vivo activity which is greater than that observed hitherto. The compounds discovered by the Applicant accordingly have anti-tumour properties that make them especially useful in the treatment of cancers and, especially, of solid tumours.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
X and Y, which may be the same or different, represent, independently of one another, a group selected from:
hydrogen and halogen atoms,
mercapto, cyano, nitro, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)-trihaloalkyl and linear or branched trihalo-(C1-C6)alkyl-carbonylamino groups,
groups of formulae xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94NRaxe2x80x94C(O)-T1, xe2x80x94Oxe2x80x94C(O)-T1, xe2x80x94O-T2-NRaRb, xe2x80x94O-T2-ORa, xe2x80x94NRa-T2-NRaRb, xe2x80x94NRa-T2-ORa and xe2x80x94NRa-T2-CO2Ra wherein:
Ra represents a group selected from a hydrogen atom and a linear or branched (C1-C6)alkyl group, an aryl group and an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched,
Rb represents a group selected from a hydrogen atom and a linear or branched (C1-C6)alkyl group, an aryl group and an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched, or
xe2x80x83Ra+Rb, together with the nitrogen atom carrying them, form a monocyclic 5- or 6-membered heterocycle optionally containing in the cyclic system a second hetero atom selected from oxygen and nitrogen,
T1 represents a group selected from linear or branched (C1-C6)alkyl, linear or branched (C2-C6)alkenyl, aryl, aryl-(C1-C6)alkyl (wherein the alkyl moiety is linear or branched), and a linear or branched (C1-C6)alkylene chain substituted by a group selected from xe2x80x94ORa and xe2x80x94NRaRb wherein Ra and Rb are as defined hereinbefore,
T2 represents a linear or branched (C1-C6)alkylene chain,
or X and Y, when they are in adjacent positions, together form a methylenedioxy group or an ethylenedioxy group,
it being understood that the substituents X and Y may be present on either of the two adjacent benzene rings,
R1 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R2 represents a group selected from a hydrogen atom and linear or branched (C1-C6)alkyl, xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94NRaxe2x80x94C(O)-T1, xe2x80x94Oxe2x80x94C(O)-T1, xe2x80x94O-T2-NRaRb, xe2x80x94O-T2-ORa, xe2x80x94NRa-T2-NRaRb, xe2x80x94NRa-T2-ORa and xe2x80x94NRa-T2-CO2Ra groups, wherein Ra, Rb, T1 and T2 are as defined hereinbefore,
R3, R4, which may be the same or different, represent, independently of one another, a hydrogen atom or a linear or branched (C1-C6)alkyl group,
W represents a group of formula xe2x80x94CH(R5)xe2x80x94CH(R6)xe2x80x94, xe2x80x94CHxe2x95x90C(R7)xe2x80x94, xe2x80x94C(R7)xe2x95x90CHxe2x80x94 or xe2x80x94C(O)xe2x80x94CH(Rd 8)xe2x80x94 wherein:
R5 and/or R6, represent(s) a group selected from xe2x80x94W1xe2x80x94C(W2)xe2x80x94W3-T1, xe2x80x94W4xe2x80x94C(W2)-Txe2x80x21, xe2x80x94W1xe2x80x94S(O)nxe2x80x94W3-T1 and xe2x80x94W1xe2x80x94S(O)nxe2x80x94T1 wherein:
W1 represents an oxygen or sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched,
W2 represents an oxygen atom or a sulphur atom,
W3 represents an oxygen or sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched C1-C6) alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched, a bond when T1 represents a linear or branched (C2-C6) alkenyl group,
W4 represents a sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched,
T1 is as defined hereinbefore,
Txe2x80x21 represents a group selected from linear or branched (C2-C6)alkenyl, aryl, aryl-(C1-C6)alkyl (wherein the alkyl moiety is linear or branched), a linear or branched (C1-C6)alkylene chain substituted by a group selected from xe2x80x94ORa and xe2x80x94NRaRb wherein Ra and Rb are as defined hereinbefore,
n represents an integer selected from 1 and 2,
xe2x80x83and in the case where only one of the two groups R5 and R6 represents a group as defined hereinbefore then the other of the said groups R5 or R6 represents a group selected from a hydrogen atom, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl-carbonyloxy, arylcarbonyloxy, aryl-(C1-C6)alkyl-carbonyloxy (wherein the alkyl moiety is linear or branched), and amino optionally substituted by one or two, identical or different, linear or branched (C1-C6)alkyl groups,
R7 represents a group selected from hydroxy, linear or branched (C1-C6)alkoxy, xe2x80x94C(W2)-T1, xe2x80x94W1xe2x80x94C(W2)xe2x80x94W3-T1, xe2x80x94W1xe2x80x94C(W2)-T1, xe2x80x94W1xe2x80x94S(O)nxe2x80x94W3-T1 and xe2x80x94W1xe2x80x94S(O)nxe2x80x94T1 wherein W1, W2, W3, T1 and n are as defined hereinbefore, or R7 may have the additional meaning of a hydrogen atom when R2 represents a group xe2x80x94O-T2-ORa and/or when X represents a hydrogen atom and Y, located in the 13-position of the naphthyl system of the pentacyclic skeleton, represents an amino group optionally substituted by one or two identical or different groups selected independently of one another from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl and linear or branched trihalo-(C1-C6)alkyl-carbonyl,
R8 represents a linear or branched (C1-C6)alkoxy or linear or branched (C1-C6)alkyl-carbonyloxy group, or may have the additional meaning of hydroxy when R2 represents a group xe2x80x94O-T2-ORa as defined hereinbefore,
to their enantiomers, diastereoisomers and N-oxides, and to addition salts thereof with a pharmaceutically acceptable acid or base.
Aryl is understood to mean a phenyl or naphthyl group optionally containing one or more, identical or different, substitutents selected from hydroxy, halogen, carboxy, nitro, amino, linear or branched (C1-C6)alkylamino, di(C1-C6)alkylamino wherein each alkyl moiety may be linear or branched, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)acyl and linear or branched (C1-C6)alkyl-carbonyloxy.
Isomers are understood to comprise optical isomers, that is to say enantiomers and diastereoisomers.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, lysine etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
According to an advantageous embodiment of the invention, preferred compounds are compounds of formula (IA): 
wherein X, Y, R1, R2, R3, R4, R5 and R6 are as defined for formula (I).
Preferred compounds of formula (IA) are compounds wherein R5 and R6 are identical and each represent a group of formula xe2x80x94W1xe2x80x94C(W2)xe2x80x94W3-T1 or xe2x80x94W1xe2x80x94S(O)n-T1 wherein W1, W2, W3, T1 and n are as defined for formula (I).
In especially interesting manner, preferred compounds of formula (IA) are compounds wherein R5 and R6 are identical and each represent a group of formula xe2x80x94W1xe2x80x94C(W2)xe2x80x94W3-T1 wherein W1 represents an oxygen atom, W2 represents an oxygen atom, W3 represents a nitrogen atom substituted by a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched and T1 is as defined for formula (I).
In another especially interesting manner, preferred compounds of formula (IA) are compounds wherein R5 and R6 are identical and each represent a group of formula xe2x80x94W1xe2x80x94S(O)n-T1 wherein W1 represents an oxygen atom, T1 is as defined for formula (I) and n is equal to 2.
According to a second advantageous embodiment of the invention, preferred compounds are compounds of formula (IB): 
wherein X, Y, R1, R2, R3, R4 and R7 are as defined for formula (I).
Preferred compounds of formula (IB) are compounds wherein R7 represents a group selected from xe2x80x94C(W2)-T1 and xe2x80x94W1xe2x80x94C(W2)-T1 wherein W1, W2 and T1 are as defined for formula (I).
In especially interesting manner, preferred compounds of formula (IB) are compounds wherein W1 represents an oxygen atom, W2 represents an oxygen atom and T1 represents a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched.
According to a third advantageous embodiment of the invention, preferred compounds are compounds of formula (IC): 
wherein X, Y, R1, R2, R3, R4 and R8 are as defined for formula (I).
Substituents R3 and R4 that are preferred according to the invention are linear or branched (C1-C6)alkyl groups.
Substituents R2 that are preferred according to the invention are groups selected from linear or branched (C1-C6)alkoxy, xe2x80x94NRaRb, xe2x80x94O-T2-NRaRb, xe2x80x94O-T2-ORa, xe2x80x94NRa-T2-NRaRb and xe2x80x94NRa-T2-ORa wherein Ra, Rb, T1 and T2 are as defined for formula (I).
According to a fourth advantageous embodiment of the invention, preferred compounds are compounds of formula (IB1): 
wherein R1, R2, R3 and R4 are as defined for formula (IB) and Y represents an amino group optionally substituted by one or two identical or different groups selected independently of one another from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl and linear or branched trihalo-(C1-C6)alkyl-carbonyl.
In especially advantageous manner, preferred compounds of the invention are:
(1S,2S)-1-{[(dimethylamino)carbonyl]oxy}-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl dimethylcarbamate,
(1S,2S)-6-methoxy-3,3,14-trimethyl-2-{[(4-methylphenyl)sulphonyl]oxy}-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-1-yl 4-methylbenzenesulphonate,
6-methoxy-3,3,14-trimethyl-7-oxo-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-2-yl acetate,
2-benzoyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]-acridin-7-one
2-butyryl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]-acridin-7-one,
2-acetyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]-acridin-7-one,
6-methoxy-3,3,14-trimethyl-7-oxo-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]-acridin-2-yl butyrate,
6-(2-hydroxyethoxy)-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]-acridin-7-one,
13-amino-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]-acridin-7-one,
N-(6-methoxy-3,3,14-trimethyl-7-oxo-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]-acridin-13-yl)acetamide,
6-methoxy-3,3-dimethyl-1,7-dioxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]-acridin-2-yl acetate.
The enantiomers, diastereoisomers, N-oxides and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds form an integral part of the invention.
The present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (VI): 
wherein X, Y, R, R3 and R4 are as defined hereinbefore,
the nitrogen atom of which compound of formula (VI) is optionally substituted, by the action of an alkyl halide or of a dialkyl sulphate in the presence of a deprotonating agent, in an aprotic polar solvent or under phase transfer conditions, yielding the compounds of formula (IX): 
wherein X, Y, R, R3 and R4 are as defined hereinbefore and Rxe2x80x21 represents a linear or branched (C1-C6)alkyl group,
which compounds of formula (IX) are subjected to the action of an alkylating agent or an acylating agent under customary conditions of organic synthesis to yield the compounds of formula (X): 
wherein X, Y, Rxe2x80x21, R3 and R4 are as defined hereinbefore and Rxe2x80x22 represents a group selected from xe2x80x94ORa, xe2x80x94Oxe2x80x94C(O)-T1, xe2x80x94O-T2-NRaRb and xe2x80x94O-T2-ORa wherein Ra, Rb, T1 and T2 are as defined for formula (I),
which compounds of formula (X), in the case where Rxe2x80x22 represents an alkoxy group, are treated with a compound of formula (XI):
HNRaR10 xe2x80x83xe2x80x83(XI), 
wherein Ra represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched, and R10 represents a group selected from Rb, xe2x80x94C(O)-T1, -T2-NRaRb, -T2-ORa and -T2-CO2Ra wherein Ra, Rb, T1 and T2 are as defined for formula (I),
to yield the compounds of formula (XII): 
wherein X, Y, Rxe2x80x21, R3, R4, Ra and R10 are as defined hereinbefore,
the totality of the compounds of formulae (VI), (IX), (X) and (XII) forming the compounds of formula (XIII): 
wherein X, Y, R1, R2, R3 and R4 are as defined in the general definition for formula (I),
which compounds of formula (XIII) are subjected:
a) either to the action of a compound of formula (XIV):
Hal-C(W2)-T1 xe2x80x83xe2x80x83(XIV), 
wherein Hal represents a halogen atom and W2 and T1 are as defined in the general definition for formula (I),
to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4, W2 and T1 are as defined hereinbefore,
b) or to the action of an oxidising agent for alkene functions to yield the compounds of formula (XV): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (XV) are treated with a compound of formula (XVI):
Hal-G1 xe2x80x83xe2x80x83(XVI), 
wherein Hal represents a halogen atom and G1 represents a group selected from xe2x80x94C(W2)xe2x80x94W3-T1, xe2x80x94C(W2)-T1, xe2x80x94S(O)nxe2x80x94W3-T1 and xe2x80x94S(O)n-T1 wherein W2, W3, T1 and n are as defined for formula (I),
to yield the compounds of formulae (I/b), (I/c) and (I/d), particular cases of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4 and G1 are as defined hereinbefore,
which compounds of formulae (I/c) and/or (I/d) are subjected:
either to the action of an alcohol of formula R20xe2x80x94OH, wherein R20 represents a linear or branched (C1-C6)alkyl group, to yield the compounds of formulae (I/c1) and (1/d1), respectively: 
wherein X, Y, R1, R2, R3, R4, G1 and R20 are as defined hereinbefore,
or to the action of an anhydride of formula (R30CO)2O, wherein R30 represents a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched, to yield the compounds of formulae (I/c2) and (I/d2), respectively: 
wherein X, Y, R1, R2, R3, R4, G1 and R30 are as defined hereinbefore,
or to dehydrating conditions in an acid medium to yield the compounds of formulae (I/c3) and (I/d3), respectively, particular cases of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4 and G1 are as defined hereinbefore,
c) or to the action of a peracid or of dimethyl dioxirane to yield the compounds of formula (XVII): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (XVII) are treated with ammoniac or with a primary amine to yield the compounds of formulae (XVIII/a) and/or (XVIII/b): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, Rc represents a hydrogen atom and Ra represents a hydrogen atom in the case where the reagent used is ammoniac or represents a group selected from linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl (wherein the alkyl moiety is linear or branched) in the case where the reagent used is a primary amine, the alcohol function of which compounds of formulae (XVIII/a) and (XVIII/b) is protected by a protecting group for hydroxy groups, the compounds then being subjected to the action of a compound of formula Hal-G1 (XVI) as defined hereinbefore to yield the compounds of formulae (XIX/a) and (XIX/b), respectively, 
wherein X, Y, R1, R2, R3, R4, Ra and G1 are as defined hereinbefore and P1 represents a protecting group for hydroxy functions,
the hydroxy group of which compounds of formulae (XIX/a) and (XIX/b) is deprotected to yield the compounds of formulae (I/e1) and (I/f1), respectively, particular cases of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4, Ra and G1 are as defined hereinbefore,
which compounds of formulae (I/e1) and (I/f1) are subjected:
either to the action of an anhydride of formula (R30CO)2O, wherein R30 represents a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group wherein the alkyl moiety is linear or branched, to yield the compounds of formulae (I/e2) and (If2), respectively, particular cases of the compounds of formula (1): 
wherein X, Y, R1, R2, R3, R4, Ra, G1 and R30 are as defined hereinbefore,
or to dehydrating conditions in an acid medium to yield the compounds of formulae (I/e3) and (I/f3), respectively, particular cases of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4, Ra and G1 are as defined hereinbefore,
d) or to the action of NaN3 in the presence of hydrogen peroxide, followed by a reduction step using tri-n-butyltin hydride, for example, to yield the compounds of formula (XX): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (XX) are subjected to the action of a compound of formula Hal-G1 (XVI) as defined hereinbefore to yield the compounds of formula (I/g), a particular case of the compounds of formula (I): 
wherein X, Y, R1, R2, R3, R4 and G1 are as defined hereinbefore,
e) or to the action of potassium permanganate in a polar medium to yield the compounds of formula (XXI): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (XXI) are subjected to the action of either an alkylating agent or an acylating agent to yield the compounds of formula (I/h), a particular case of the compounds of formula (I): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore and R40 represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)acyl group,
or the hydroxy functions of which compounds of formula (XXI) are protected with a protecting group conventionally used in organic synthesis, the compounds then being subjected to the action of P2S5 to yield the compounds of formula (XXII): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore and P1 represents a protecting group for hydroxy functions,
which compounds of formula (XXII) are treated with a reducing agent and then subjected to a reaction for deprotection of the hydroxy function to yield the compounds of formula (XXIII): 
wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (XXIII) are treated with a compound of formula (XVI) as defined hereinbefore to yield the compounds of formula (I/i), a particular case of the compounds of formula (I): 
wherein X, Y, G1, R1, R2, R3 and R4 are as defined hereinbefore,
which compounds of formula (I/i) may be subjected to the action of an alkylating agent, an acylating agent or a compound of formula (XVIa):
Hal-Gxe2x80x21xe2x80x83xe2x80x83(XVIa), 
wherein Hal represents a halogen atom and Gxe2x80x21 represents a group selected from xe2x80x94C(W2)xe2x80x94W3-T1, xe2x80x94C(W2)-T1, xe2x80x94S(O)nxe2x80x94W3-T1 and xe2x80x94S(O)n-T1, wherein W2, W3, T1 and n are as defined for formula (I),
to yield the compounds of formula (I/j), a particular case of the compounds of formula (I): 
wherein X, Y, G1, R1, R2, R3 and R4 are as defined hereinbefore and G2 represents a group selected from Gxe2x80x21 as defined hereinbefore, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl-carbonyloxy, arylcarbonyloxy and aryl-(C1-C6)alkyl-carbonyloxy (wherein the alkyl moiety is linear or branched),
the compounds of formulae (I/a) to (I/j), (I/c1) to (I/c3), (I/d1) to (I/d3), (I/e1) to (I/e3) and (I/f1) to (I/f3) constituting the totality of the compounds of the invention, which are purified, if necessary, according to a conventional purification technique, which may be, if desired, separated into their different isomers according to a conventional separation technique and which are converted, if desired, into their N-oxides and, where appropriate, their addition salts with a pharmaceutically acceptable acid or base.
The compounds of formula (VI) may advantageously be obtained:
either starting from 3-amino-2-naphthalenecarboxylic acid compounds (II): 
wherein X and Y are as defined for formula (I),
which are reacted with a phloroglucinol compound of formula (III): 
wherein R represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6)alkyl group,
to yield the compounds of formula (IV): 
wherein X, Y and R are as defined hereinbefore,
which are then treated under basic conditions in an aprotic solvent with an alkyne of formula (V): 
wherein Hal represents a halogen atom and R3 and R4 are as defined for formula (I),
to yield the compounds of formula (VI) as defined hereinbefore,
or starting from 3-halo-2-naphthalenecarboxylic acid compounds of formula (VII): 
wherein X and Y are as defined for formula (I) and Hal represents a halogen atom,
which are reacted with an amino-chromene compound of formula (VIII): 
wherein R3 and R4 are as defined for formula (I) and R is as defined hereinbefore,
to yield, likewise, the compounds of formula (VI) as defined hereinbefore.
The compounds of formula (XIII) are synthesis intermediates that are useful in obtaining the compounds of formula (I). Among those compounds of formula (XIII) there are distinguished:
compounds of formula (IB1): 
wherein R1, R2, R3 and R4 are as defined for formula (IB) and Y represents an amino group optionally substituted by one or two identical or different groups selected independently of one another from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl and linear or branched trihalo-(C1-C6)alkyl-carbonyl,
and compounds of formula (IB2): 
wherein R1, R3, R4, T2, Ra, X and Y are as defined for formula (I).
Those compounds of formulae (IB1) and (IB2) are new and have cytotoxic activity. They are therefore useful in the treatment of cancers.
The compounds of formula (XXI) likewise are synthesis intermediates that are useful in obtaining the compounds of formula (I) and, more especially, compounds of formula (IC). Those compounds of formula (XXI) likewise have cytotoxic activity. Their use as an active ingredient in a pharmaceutical composition makes the latter useful in the treatment of cancers.
The compounds of formulae (II), (III), (V), (VII), (VIII), (XI), (XIV) and (XVI) either are commercially available compounds or are obtained according to conventional methods of organic synthesis well known to the person skilled in the art.
The compounds of formula (I) have especially valuable anti-tumour properties. They have excellent in vitro cytotoxicity with respect to cell lines originating from murine and human tumours, by virtue of specific blockage of the cell cycle, and are active in vivo, in the mouse, with respect to transplantable murine and human tumours. The characteristic properties of these compounds allow them to be used therapeutically as anti-tumour agents.
The present invention relates also to pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I), an enantiomer or diastereoisomer thereof, or an N-oxide thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
Pharmaceutical compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions and also sterile powders for reconstituting injectable solutions or dispersions.
Pharmaceutical compositions according to the invention for solid oral administrations especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, and for liquid oral, nasal, buccal or ocular administrations especially include emulsions, solutions, suspensions, drops, syrups and aerosols.
Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointments, gels and patches.
The pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
Among the inert, non-toxic, pharmaceutically acceptable excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colourants, aromatising agents etc.
The useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments. The dosage ranges from 0.1 mg to 1000 mg per day in one or more administrations.
The Examples that follow illustrate the invention but do not limit it in any way.
The starting materials used are products that are known or that are prepared according to known operating procedures. The various Preparations yield synthesis intermediates that are useful in preparation of the compounds of the invention.
The structures of the compounds described in the Examples and Preparations were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, . . . ).
The melting points were determined using either a Kofler hot-plate or a hot-plate under a microscope. When the compound is in the form of a salt, the melting point given refers to the salt form of the compound.
Step A: 1,3-Dihydroxy-5,12-dihydro-benzo[b]acridin-12-one
To a solution of 5 g of 3-amino-2-naphthalenecarboxylic acid in 50 ml of heptan-1-ol there are added 3.5 g of 1,3,5-trihydroxybenzene and 62.5 mg of para-toluenesulphonic acid. The mixture is stirred for 48 hours under reflux using a Dean-Stark apparatus, and the reaction mixture is then concentrated in vacuo. The residue is chromatographed over silica gel (eluant:cyclohexane/acetone: 90/10). The isolated product is crystallised from a cyclohexane/acetone mixture, allowing 5.2 g of the expected product to be obtained.
Step B: 6-Hydroxy-3,3-dimethyl-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-7-one
To a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide, under an inert atmosphere, there are added 2 g of anhydrous potassium carbonate. After stirring for 15 minutes at 65xc2x0 C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyne are added, and the reaction mixture is held at 65xc2x0 C. for 24 hours and then at 130xc2x0 C. for 1 hour. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with 1M potassium hydroxide solution, dried over sodium sulphate and then evaporated. After chromatography over silica gel (cyclohexane/acetone: 90/10), 1.10 g of the expected product are isolated.
Melting point: 225xc2x0 C.
Step C: 6-Methoxy-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]pyrano-[3,2-h]acridin-7-one
To a solution of 0.5 g of the product obtained in Step B in 20 ml of anhydrous dimethylformamide there are slowly added, at 0xc2x0 C., under an inert atmosphere, 0.16 g of sodium hydride and then, after 15 minutes, 0.65 ml of dimethyl sulphate (6 equivalents). After 1 hour, the reaction mixture is hydrolysed using ice and is then extracted with ethyl acetate. After washing the organic phase with aqueous sodium hydroxide solution, it is dried over sodium sulphate and then evaporated in vacuo. Chromatography over silica gel (cyclohexane/acetone: 98/2) allows 0.42 g of the expected product to be obtained. Melting point: 188xc2x0 C.
To a solution of 2 g of the product of Preparation 1 and 0.9 g of 4-methylmorpholine-N-oxide monohydrate in 40 ml of a mixture of tert-butanol/tetrahydrofuran/water (10/3/1) there is added osmium tetroxide in the form of a 2.5% solution in 3.8 ml of 2-methyl-2-propanol. After 2 days at ambient temperature, 105 ml of saturated NaHSO3 solution are added, and the mixture is stirred for 1 hour and then extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. Chromatography over silica gel (dichloromethane/methanol: 95/5) allows 1.3 g of the expected product to be isolated.
Melting point: 194xc2x0 C.
To 0.15 g of the product of Preparation 1 there are added 4 ml of N,N-diethyl-propylenediamine. After reacting for 5 days at 70xc2x0 C. under an inert atmosphere, the reaction mixture is evaporated under reduced pressure. The residue obtained is chromatographed over silica gel (cyclohexane/ethyl acetate: 80/20), allowing the expected product to be isolated.
Mass spectrum: (DIC/NH3): m/z: 470 (M+H)+
The procedure is as in Preparation 3, using 4-(2-aminoethyl)-morpholine as reagent.
Mass spectrum: (DIC/NH3): m/z: 470 (M+H)+
The procedure is as in Preparation 2, using the compound of Preparation 3 as substrate.
Step A: (xc2x1)-1-Azido-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-7-one
To a solution of 0.15 g of the compound of Preparation 2 and 0.5 g of NaN3 in 6 ml of chloroform there are slowly added, at ambient temperature, 3 ml of trifluoroacetic acid. After stirring for 12 hours, 1 equivalent of NaN3 is added and the reaction mixture is held at ambient temperature for a further 12 hours. The reaction mixture is then washed with water and then with saturated NaCl solution and is dried over sodium sulphate. Chromatography over silica gel (dichloromethane/methanol: 95/5) allows the expected product to be isolated.
Step B: (xc2x1)-1-Amino-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-7-one
A solution containing 0.2 g of the compound obtained in Step A and 0.09 g of Pd/C in 5 ml of ethanol is stirred at ambient temperature under an H2 atmosphere for 48 hours. The catalyst is then filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed over silica (dichloromethane/methanol: 95/5), allowing the desired product to be isolated.
Step A: 6-Hydroxy-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-7-one
The product is obtained according to the procedure of Preparation 1, using only 1.5 equivalents of sodium hydride and 2 equivalents of dimethyl sulphate.
Melting point: 138xc2x0 C.
Step B. 6-(Dimethylaminoethyloxy)-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]-pyrano[3,2-h]acridin-7-one
To a solution, under nitrogen, of 0.2 g of the compound obtained in Step A in 20 ml of dimethylformamide, there are added 1 equivalent of sodium hydride and 1 equivalent of 2-dimethylaminoethyl chloride hydrochloride. After 48 hours at 70xc2x0 C., the reaction mixture is cooled; it is then poured onto 80 ml of ice-cold water and extracted with dichloromethane. After washing and drying over MgSO4, the solution is evaporated under reduced pressure. Chromatography over silica gel (ethyl acetate/cyclohexane: 80/20) allows the expected product to be isolated.
Mass spectrum: (DIC/NH3): m/z: 429 (M+H)+
Chromatography over silica gel allows isolation of this co-product, which forms during synthesis of the compound of Preparation 6.